title: Greatwall is essential to prevent mitotic collapse after nuclear envelope breakdown in mammals.
abstract: Greatwall is a protein kinase involved in the inhibition of protein phosphatase 2 (PP2A)-B55 complexes to maintain the mitotic state. Although its biochemical activity has been deeply characterized in Xenopus, its specific relevance during the progression of mitosis is not fully understood. By using a conditional knockout of the mouse ortholog, Mastl, we show here that mammalian Greatwall is essential for mouse embryonic development and cell cycle progression. Yet, Greatwall-null cells enter into mitosis with normal kinetics. However, these cells display mitotic collapse after nuclear envelope breakdown (NEB) characterized by defective chromosome condensation and prometaphase arrest. Intriguingly, Greatwall is exported from the nucleus to the cytoplasm in a CRM1-dependent manner before NEB. This export occurs after the nuclear import of cyclin B-Cdk1 complexes, requires the kinase activity of Greatwall, and is mediated by Cdk-, but not Polo-like kinase 1-dependent phosphorylation. The mitotic collapse observed in Greatwall-deficient cells is partially rescued after concomitant depletion of B55 regulatory subunits, which are mostly cytoplasmic before NEB. These data suggest that Greatwall is an essential protein in mammals required to prevent mitotic collapse after NEB.
authors.affiliation: Cell Division and Cancer Group, Spanish National Cancer Research Centre, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Álvarez-Fernández
authors.forename: Ruth
authors.initials: R
authors.lastname: Sánchez-Martínez
authors.forename: Belén
authors.initials: B
authors.lastname: Sanz-Castillo
authors.forename: Pei Pei
authors.initials: PP
authors.lastname: Gan
authors.forename: María
authors.initials: M
authors.lastname: Sanz-Flores
authors.forename: Marianna
authors.initials: M
authors.lastname: Trakala
authors.forename: Miguel
authors.initials: M
authors.lastname: Ruiz-Torres
authors.forename: Thierry
authors.initials: T
authors.lastname: Lorca
authors.forename: Anna
authors.initials: A
authors.lastname: Castro
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005260:Female; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008322:Mammals / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D009685:Nuclear Envelope / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D013997:Time Factors
chemical_list: D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D021122:Protein Subunits; D017346:Protein Serine-Threonine Kinases; C585164:greatwall protein, mouse; D054648:Protein Phosphatase 2
keywords: cell cycle regulation; cell division; mitotic kinases; mitotic phosphatases; nuclear export